Down syndrome (DS) is a well‐known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. In this retrospective biomarker discovery study, we examined banked peripheral plasma samples from 78 individuals with DS who met clinical criteria for AD at the time of the blood draw (DS‐AD) and 68 individuals with DS who did not (DS‐NAD). We measured the relative abundance of approximately 5,000 putative features in the plasma using untargeted mass spectrometry (MS). We found significantly higher levels of a peak putatively annotated as lactic acid in the DS‐AD group (q = .014), a finding confirmed using targeted MS (q = .011). Because lactate is the terminal product of glycolysis and subsequent lactic acid fermentation, we performed additional targeted MS focusing on central carbon metabolism which revealed significantly increased levels of pyruvic (q = .03) and methyladipic (q = .03) acids in addition to significantly lower levels of uridine (q = .007) in the DS‐AD group. These data suggest that AD in DS is accompanied by a shift from aerobic respiration toward the less efficient fermentative metabolism and that bioenergetically derived metabolites observable in peripheral blood may be useful for detecting this shift.

中文翻译：

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在患有唐氏综合症和阿尔茨海默氏病的成年人中，与细胞能量代谢有关的血浆代谢物发生了改变。

唐氏综合症（DS）是一种众所周知的神经发育障碍，最常见是由21号染色体三体性引起的。由于患有DS的个体几乎普遍发展出沉重的淀粉样蛋白负荷和阿尔茨海默氏病（AD），因此在这一人群中发现生物标志物可能会非常有成果。此外，DS中任何不直接涉及淀粉样蛋白病理的AD生物标志物对于理解可推广至神经型人群的更广泛的AD机制可能具有很高的价值。在这项回顾性生物标志物发现研究中，我们检查了来自78名在抽血时符合AD临床标准的DS患者（DS-AD）和68名没有DS的DSDS-NAD患者的外周血浆样本。我们使用非目标质谱（MS）测量了血浆中大约5,000个假定特征的相对丰度。q  = .014），使用目标MS确认的发现（q  = .011）。由于乳酸是糖酵解和随后的乳酸发酵的最终产物，因此我们进行了针对中心碳代谢的其他靶向质谱分析，除了显着增加丙酮酸（q  = .03）和甲基 己二酸（q = .03）的水平， 在DS‐AD组中尿苷水平较低（q = .007）。这些数据表明，DS中的AD伴随有氧呼吸从有氧呼吸向低效的发酵代谢转变，并且在外周血中可观察到的生物能源衍生代谢产物可用于检测这种转变。